Letrozole, the active ingredient in the product Femara®, is a nonsteroidal aromatase inhibitor, which has the chemical name 4-[α-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]-benzonitrile, and the following structural formula (I):

Letrozole was developed for treatment of advanced breast cancer in postmenopausal women with disease progression following anti-estrogen therapy, especially for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer.
The endosynthesis of estrogen in postmenopausal women is mediated by the aromatase enzyme, which converts androstenedione and testosterone and other androgens into estradiol and estrone. Letrozole inhibits the biosynthesis of estrogen from adrenal androgens (thus causing reduction in estrogen levels) by competitive binding to the heme portion of the cytochrome P450 subunit of aromatase. This binding reduces estrogen production, which significantly lowers serum estrogens. The suppression of estrogen may decrease the stimulatory effects of estrogen on tumor growth in estrogen-responsive tumors. Letrozole reportedly exerts no clinically relevant detectable effect on the synthesis of adrenal corticosteroids and aldosterone or on thyroid function.
U.S. Pat. No. 4,978,672 (“the '672 patent”) describes a process for preparing letrozole by reacting α-bromo-4-tolunitrile with 1,2,4-triazole to produce 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile, and reacting the product with 4-fluorobenzonitrile to obtain letrozole.
U.S. Pat. No. 5,473,078 (“the '078 patent”) describes a method for preparing 4-[1-(1,2,4-triazolyl)methyl]benzonitrile by refluxing a solution of c-bromo-4-tolunitrile with 1,2,4-triazole for 15 hours in a mixture of acetonitrile and chloroform. The intermediate is purified by chromatography on silica gel, eluting with chloroform and isopropanol, and then reacted with 4-fluorobenzonitrile and potassium tert-butoxide in DMF, to obtain letrozole. An exemplary process described in the '078 patent is generally depicted in Scheme 1.

The processes described in the '672 and '078 patents are problematic in that the first step produces considerable quantities of the undesired isomer 4-[1-(1,3,4-triazolyl)-methyl]-benzonitrile, which has the following structural formula (II):

Methods for addressing the problem of forming the 1,3,4-isomer (II) have been reported. For instance, application WO 2005/047269 describes a precipitation process for separating the desired intermediate (4-[1-(1,2,4-triazolyl)methyl]-benzonitrile) from the 1,3,4-isomer (II). However, this method requires an extra step of purification at an intermediate stage in the synthesis, which can be impractical on an industrial scale.
International patent application WO 2004/076409 (“the '409 application”) describes a regioselective process for preparing letrozole, which includes reacting 4-halomethyl-benzonitrile with 4-amino-1,2,4-triazole followed by deamination and reaction with 4-fluorobenzonitrile. The process described in the '409 application is generally depicted in Scheme 2.

The '409 application teaches that the process described in the '672 patent produces the unwanted isomer of formula II (20-40%) in the first step, and upon treating the product with 4-fluoro-benzonitrile, produces letrozole and 4-[α-(4-cyanophenyl)-1-(1,3,4-triazolyl)methyl]-benzonitrile (hereinafter “isoletrozole”), which has the structural formula (III):

While the process described in the '409 application is said to avoid formation of the unwanted isomers (II) and (III), the synthetic route requires an additional step of deamination with sodium nitrite and hydrochloric acid. Further, reacting sodium nitrite with hydrochloric acid produces nitrous acid, which is toxic and can create an explosion hazard. As such, the process described in the '409 application has limited potential for industrial application.
There is a need for an improved, industrially viable process for the large scale preparation of highly pure letrozole. The present invention provides such a process.